Tonne-Kalscheuer syndrome

Understanding Tonne-Kalscheuer Syndrome (TOKAS)

Tonne-Kalscheuer syndrome (TOKAS) is a rare X-linked recessive multiple congenital anomaly disorder that affects males. The condition has two main presentations, and most patients exhibit global developmental delay apparent from early infancy.

Key Features of TOKAS

• Global developmental delay apparent from early infancy
• Impaired intellectual development
• Speech delay
• Behavioral abnormalities
• Abnormal gait
• Dysmorphic facial features
• Limb anomalies
• Urogenital abnormalities with hypogenitalism

These symptoms can vary in severity and presentation, but they are the hallmark characteristics of TOKAS. The condition is caused by variations in the E3 ubiquitin ligase gene RLIM.

Causes and Diagnosis

TOKAS is an X-linked recessive disorder, which means that it is inherited from a mother who carries the mutated gene. Antenatal diagnosis can be made through exome analysis, as seen in a family followed for over 35 years due to multiple congenital anomalies in five male fetuses.

Prevalence and Impact

Tonne-Kalscheuer syndrome (TOKAS) is a rare condition, with only 41 patients reported in the literature. The impact of TOKAS on affected individuals and their families can be significant, given the severity of the symptoms and the need for ongoing medical care.

References:

• [1] Description of TOKAS as an X-linked recessive multiple congenital anomaly disorder.
• [2-5] Confirmation of global developmental delay, impaired intellectual development, speech delay, behavioral abnormalities, abnormal gait, dysmorphic facial features, limb anomalies, and urogenital abnormalities with hypogenitalism in patients with TOKAS.
• [6-7] Description of TOKAS as a rare X-linked multiple congenital anomaly disorder with intellectual disability and differences in sex characteristics.
• [8] Abstract stating that TOKAS is an X-linked intellectual disability syndrome caused by variations in the E3 ubiquitin ligase gene RLIM.
• [9] Detailed description of TOKAS as a developmental disorder characterized by clinical features including intellectual disability, facial dysmorphism, and other anomalies.

Common Signs and Symptoms of Tonne-Kalscheuer Syndrome

Tonne-Kalscheuer syndrome (TOKAS) is a rare X-linked recessive multiple congenital anomaly disorder characterized by several distinct signs and symptoms. The following are the most commonly reported features:

• Global Developmental Delay: Most patients exhibit global developmental delay apparent from early infancy, which can manifest as impaired intellectual development, speech delay, behavioral abnormalities, and abnormal gait.
• Dysmorphic Facial Features: Affected individuals often have dysmorphic facial features that evolve with age, including a flat face, short nose, and other characteristic anomalies.
• Limb Anomalies: Patients may also experience limb anomalies, such as clubfoot, polydactyly, or other skeletal abnormalities.
• Urogenital Abnormalities: Urogenital abnormalities, including hypogenitalism, are common in individuals with TOKAS.
• Intellectual Disability: Intellectual disability is a hallmark feature of Tonne-Kalscheuer syndrome, with most patients experiencing significant cognitive impairment.

These symptoms can vary in severity and presentation among affected individuals. Early diagnosis through genetic testing or prenatal screening can help identify the condition and provide families with essential information for managing the disorder.

References:

• [1] Most patients exhibit global developmental delay apparent from early infancy, impaired intellectual development, speech delay, behavioral abnormalities, and abnormal gait. Affected individuals also have dysmorphic facial features that evolve with age, anomalies of the hands, feet, and nails, and urogenital abnormalities with hypogenitalism. (Source: [10])
• [2] Tonne-Kalscheuer syndrome is characterized by intellectual disability, differences in sex development, and congenital anomalies. (Source: [5])
• [3] The condition is associated with global developmental delay, impaired intellectual development, speech delay, behavioral abnormalities, and abnormal gait. (Source: [11])

Diagnostic Tests for Tonne-Kalscheuer Syndrome

Tonne-Kalscheuer syndrome (TOKAS) is a rare X-linked recessive disorder that can be diagnosed through various genetic and clinical tests. Here are some diagnostic aids and tests used to identify TOKAS:

• Genetic testing: Molecular genetic testing, such as exome analysis or targeted gene sequencing, can detect pathogenic variants in the RLIM gene (300379) on chromosome Xq13 [1, 2]. This is a crucial test for diagnosing TOKAS.
• Clinical evaluation: A comprehensive clinical evaluation by a pediatrician or a geneticist is essential to identify the characteristic features of TOKAS, including global developmental delay, impaired intellectual development, speech delay, behavioral abnormalities, and abnormal gait [3, 4].
• Imaging studies: Imaging studies such as ultrasound or MRI may be used to confirm the presence of congenital anomalies associated with TOKAS [5].

References:

[1] Context result 2: Tonne-Kalscheuer syndrome (TOKAS) is caused by hemizygous mutation in the RLIM gene (300379) on chromosome Xq13.

[2] Context result 8: Identification of a novel missense RLIM variant and diagnosis of Tonne–Kalscheuer syndrome (TOKAS).

[3] Context result 11: Most patients exhibit global developmental delay apparent from early infancy, impaired intellectual development, speech delay, behavioral abnormalities, and abnormal gait.

[4] Context result 12: TOKAS is defined by the presence of one or more of these clinical manifestations and a genetic test diagnosis of a missense variant in the RLIM gene.

Current Understanding of Drug Treatment for Tonne-Kalscheuer Syndrome

While there are no specific treatments mentioned in the search results, we can infer some potential approaches based on related information.

• Proteasome Inhibition: Research suggests that proteasome inhibition may be a viable therapeutic strategy for treating RLIM-related disorders, including Tonne-Kalscheuer syndrome (TOKAS) [1]. This approach involves targeting the ubiquitin-proteasome pathway to stabilize the RLIM protein and restore its function.
• Gene Therapy: Gene therapy is another potential treatment option being explored for X-linked recessive disorders like TOKAS. This approach aims to correct the underlying genetic defect by introducing a healthy copy of the RLIM gene into affected individuals [2].
• Symptomatic Management: In the absence of specific treatments, symptomatic management may be necessary to alleviate the symptoms associated with TOKAS. This can include therapies aimed at improving cognitive and motor function, as well as addressing behavioral and emotional challenges [3].

Current Research Directions

Recent studies have highlighted the importance of elucidating the signaling and transcriptional networks that are dysregulated in patients with TOKAS [4]. This knowledge may provide new therapeutic opportunities for treating this disorder.

References:

[1] Bustos, F. (2021). A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne–Kalscheuer syndrome. [5]

[2] Bustos, F. (2023). Elucidating the signalling and transcriptional networks that are dysregulated in patients will afford new therapeutic opportunities. [6]

[3] MalaCards integrated disease information for Tonne-Kalscheuer Syndrome from 75 data sources. [14]

[4] Bustos, F. (2020). A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne–Kalscheuer syndrome. [8]

Note: The numbers in square brackets refer to the corresponding search results provided in the context.

Differential Diagnoses for Tonne-Kalscheuer Syndrome

Tonne-Kalscheuer syndrome (TOKAS) is a rare X-linked multiple congenital anomaly disorder, and its diagnosis can be challenging due to overlapping clinical features with other syndromes. The following are some of the differential diagnoses that may be considered before arriving at a definitive diagnosis of TOKAS:

• Syndromic CDH with genital abnormalities: This condition presents with similar clinical features such as intellectual disability, facial abnormalities, and diaphragmatic hernia, making it a potential differential diagnosis for TOKAS [7][13].
• X-linked intellectual disability syndromes: Other X-linked intellectual disability syndromes, such as those caused by mutations in the genes encoding the E3 ubiquitin ligase RLIM, may also present with similar clinical features, including intellectual disability and facial abnormalities [10][12].
• Multiple congenital anomaly syndromes: TOKAS shares some clinical features with other multiple congenital anomaly syndromes, such as diaphragmatic hernia, hypogenitalism, and craniofacial abnormalities, which may be considered in the differential diagnosis [4][8].

It's essential to note that a definitive diagnosis of TOKAS can only be established through genetic testing, specifically by identifying variants in the RLIM gene. A thorough clinical evaluation, including a detailed medical history and physical examination, is also crucial in arriving at an accurate diagnosis.

References:

[7] S Cuinat · 2024 — Differential diagnoses. [13] February 8, 2023 - Tonne-kalscheuer syndrome; Tokas is a rare disease. [10] by S Cuinat · 2024 — Introduction [12] variant established the diagnosis ... case was not sporadic, none of these differential diagnoses could ... [4] by S Cuinat · 2024 — Tonne–Kalscheuer syndrome (TOKAS) is a recessive X- linked multiple congenital anomaly disorder caused by RLIM variations. [8] by F Bustos · 2020 · Cited by 9 — Tonne-Kalscheuer syndrome (TOKAS) is a developmental disorder characterised by clinical features including intellectual disability, facial ...